Habituation is a basic, ubiquitous form of learning and memory. Nonetheless, the neurobiological basis of habituation in mammals, including man, is poorly understood. This situation is largely due to the vast complexity of the mammalian central nervous system. The long-term goal of this project is to use a simple, model organism, the marine snail Aplysia californica, to elucidate the cellular and molecular basis of habituation, particularly long-term habituation (LTH). When tactile stimuli are applied to the body surface of Aplysia, the animal exhibits with a defensive withdrawal reflex. In response to repeated tactile stimulation the reflex habituates. The withdrawal reflex exhibits both short- and long-term habituation. A major advantage of the withdrawal reflex for a study of habituation is that the neural circuitry that underlies the withdrawal reflex is well characterized. The proposed research will use a reduced preparation of Aplysia that can facilitate relating synaptic changes to behavioral changes. The synapse between the sensory and motor neurons that mediate the withdrawal reflex exhibits a form of long-term depression (LTD); this LTD may play a role in LTH in Aplysia. The potential role of LTD in LTH will be tested with electrophysiological and pharmacological experiments. In other experiments the cellular and molecular mechanisms of LTD will be characterized. One intriguing possibility is that LTD involves down-regulation of the function of a class of postsynaptic glutamate receptors (AMPA receptors). Functional down-regulation of AMPA receptors, perhaps due to changes in protein or mRNA synthesis, may also play a role in LTH. Pharmacological and, ultimately, molecular techniques will be used to test this idea. It is expected that the findings from the proposed research will contribute to a fundamental understanding of the processes that underlie learning and memory. Such an understanding will facilitate the development of treatments of diseases of memory, such as Alzheimer's.